Use of incense or hydrogenation products for preventing and/or treating a cerebral ischemia and/or cerebral traumatic lesion

ABSTRACT

The invention relates to the use of the hydrogenation products of frankincense (olibanum), its hydrogenated ingredients as well as physiologically acceptable salts and derivatives thereof and hydrogenated frankincense extracts for the production of a medicament for the prophylactic and/or therapeutic treatment of cerebral ischemia, cranial/brain trauma and/or Alzheimer&#39;s disease. The use of frankincense, frankincense extract, substances contained in frankincense, their physiologically acceptable salts, their derivatives and the physiological salts thereof, pure boswellic acids, tirucallic acids or other triterpenes, their physiologically acceptable salts, derivatives of the salts thereof for the production of a medicament for the prophylactic and/or therapeutic treatment of cerebral ischemia and/or cranial/brain trauma is also provided according to the invention.

The invention relates to the use of frankincense or components thereof,which may be hydrogenated, where appropriate, for preventing and/ortreating cerebral ischemia and/or cranial/brain trauma. It has also beenfound that the hydrogenation products of frankincense or the componentsthereof are particularly advantageous in preventing and/or treatingAlzheimer's disease.

The invention thus relates in particular to the use of the hydrogenationproducts of frankincense (olibanum), its hydrogenated ingredients aswell as physiologically acceptable salts and derivatives thereof for theproduction of a medicament for preventing and/or treating cerebralischemia, cranial/brain trauma and/or Alzheimer's disease. The inventionalso relates to the use of frankincense or components of frankincensefor the production of a medicament for preventing and/or treatingcerebral ischemia and/or cranial/brain trauma (traumatic brain injury,TBI).

Ischemia is the interrupted supply of blood to cells, tissues or organs.This situation is critical in particular if a continuous supply withoxygen and/or nutrients (e.g. glucose) is necessary. This applies inparticular to the central nervous system (CNS), since the very nervecells extremely respond to an interruption of oxygen and glucosesupplies. Short-term ischemia, e.g. as a result of an apoplexy or acardiac infarction, already results in neuronal cell death in theaffected brain centers.

The cellular mechanisms of ischemia-induced lesion processes are complexand have been comprehended insufficiently in their complexity to date.Thus, effective preventive measures and therapies are problematic.

A cranial/brain trauma is understood to mean a combined injury of scalp,cranium and brain, the outer cover possibly remaining intact. Adistinction is generally made between an open cranial/brain trauma and aclosed cranial/brain trauma, the dura being destroyed in an opencranial/brain trauma with fluid and/or brain substance escaping. Theblunt or closed brain trauma differs therefrom in so far as the dura isnot destroyed.

The skull and/or brain injuries accompanying a cranial/brain traumaincrease the intracranial pressure thus damaging various brain centers.Neuronal lesion processes indicated in such a way can influencecognitive, patient's physical and psychic properties, the cellularmechanisms of traumatic lesion processes being complex and onlycomprehend insufficiently in their complexity to date.

Although various therapeutic methods are known for cerebral ischemia orcranial/brain trauma, there is a considerable need for a therapeuticmethod preventing in particular nerve cells from dieing off and, in thecase of a cranial/brain trauma, in particular also the occurrence oftrauma-induced lesions.

Alzheimer's disease is a degenerative disease causing morphological andbiochemical changes of brain centers. It is a progressive atrophy of thecerebral cortex with senile plaques, degeneration of neurofibrils andcongophilic angiopathy. The symptoms of Alzheimer's disease are interalia disorientation accompanied by disturbances of cognitive ability,memory decay, total regression up to dementia. A disturbance of thecortical cholinergic system accompanied by a reduction of cholineacetylase (reduced acetylcholine synthesis) is inter alia detectablebiochemically.

The causes of the development of Alzheimer's disease are unclear, withgenetic, metabolic or even slow virus infections being predominantlydiscussed. Therapeutic agents having specific actions are not yetavailable. The therapeutic possibilities extend above all to thealleviation of symptoms caused by the diseases. In order to treatAlzheimer's disease, e.g. the choline esterase inhibitor tacrin is used,which shall improve cognitive performance. However, a therapy using thisactive substance is unsatisfactory because of its small response rateand its strong side-effects. Therefore, there is a strong demand for atherapeutic method which at least delays the brain atrophy progressionin Alzheimer's patients. There is also a demand for a medicament whoseactive substance is highly available at the target organ (brain) andwhich is well tolerated, particularly in long-term therapy.

The use of frankincense is already known in folk medicine for treatingthe most different diseases, in particular inflammations and rheumatism,above all in Chinese and Indian folk medicine.

Frankincense or olibanum is understood to mean a gum resin which can beobtained from the bark of the trees Boswellia carteri, Boswellia serrataand other species domiciled in Arabia and Somalia. The resin usuallycontains 5 to 9% olibanum oil (or frankincense oil), 15 to 16% gumacids, 25 to 30% compounds insoluble in ether, and 45 to 55% compoundssoluble in ether, in particular the triterpenoid boswellic acids, mostlythe β-boswellic acid. Boswellic acid is also often referred to asboswellia acid in the literature.

A mixture of the resins of the balsam trees Boswellia sacra (SouthArabia), Boswellia carteri and Boswellia frereana (both Somalia) is alsooften referred to as frankincense or olibanum. The Indian frankincense(“Salai Guggal”) is also known. It is obtained from extracts of theBoswellia serrata resin (India). Salai Guggal is a vegetable mixture ofmany substances. It contains ethereal oils (various mono-,di-sesquiterpenes), mucilages (inter alia galactose, arabinose, mannose,xylose), and the resinous substances pharmacologically effectiveaccording to today's standard of knowledge (pentacyclic and tetracyclictriterpenes, boswellic acids or tirucallic acids). Following extractionwith lipophilic solvents according to special methods (see below), whatis called a “standardized Indian frankincense dry extract” is obtained.

Pardhy & Bhattacharyya report in Ind. J. Chem., 16 b: 176-178, 1978,that Boswellia serrata substantially contains the following ingredients:β-boswellic acid, acetyl-β-boswellic acid, acetyl-11-keto-β-boswellicacid, 11-keto-β-boswellic acid and small portions of α- and β-boswellicacid and the tirucallic acids.

In the recent past, several medical applications were found forfrankincense or frankincense extract and in particular for boswellicacid and the derivatives thereof.

For example, WO 90/01937 reports that α-boswellic acid acetate andβ-boswellic acid acetate and the analogs thereof inhibit topoisomerase Iand topoisomerase II. Therefore, this publication proposes that thecompounds be used for treating various types of cancer.

DE-A 42 01 903 and its equivalent EP-A 552 657 disclose that pureboswellic acid, physiologically acceptable salts thereof, derivativesthereof and salts of the derivatives or a boswellic acid-containing,vegetable preparation may combat inflammatory processes caused by anincreased leukotriene formation. Therefore, said publications proposethat the compounds be used in particular for treating inflammatoryarthropathies, epidermal lesions, allergic and chronic asthma, endotoxinshock, inflammatory bowel diseases and chronic hepatitis.

DE-A 44 44 288 and its equivalent EP-B 0 796 103 disclose thatfrankincense, frankincense extracts, substances contained infrankincense, their physiologically acceptable salts, their derivativesand the physiological salts thereof, pure boswellia acid, aphysiologically acceptable salt, a derivative and a salt of thederivative can be used for treating Alzheimer's disease.

DE-A 44 45 728 uses pure boswellic acid, physiologically acceptablesalts thereof, derivatives thereof or salts of the derivatives andvegetable preparations containing a boswellic acid for the treatment ofbrain tumors.

WO 97/07796 uses boswellia acid, a physiologically acceptable salt, aderivative, a salt of the derivative or a boswellic acid-containingvegetable preparation for preventing and/or combating diseases which arecaused by an increased leukocyte elastase or plasmin activity.Therefore, this publication proposes the use of compounds for treatingdiseases, such as pulmonary emphysema, acute respiratory distresssyndrome, shock lung, cystic fibrosis, chronic bronchitis,glomerulonephritis and rheumatic arthritis, as well as for inhibitingthe growth and metastasis formation of many types of tumor.

WO 02/15916 and DE-A 100 41 217 constituting its priority disclosedihydroboswellia acids, physiologically acceptable salts thereof andhydrogenated extracts from boswellia. Said publications suggest the useof these compounds for the prophylactic and/or therapeutic treatment ofundesired physical and psychic conditions, in particular of somatic,psychosomatic and psychic diseases, such as inflammatory processescaused by increased leukotriene formation, leukocyte elastase or plasminactivity. The above-mentioned diseases are e.g. inflammatoryarthropathies, epidermal lesions, allergic and chronic asthma, endotoxinshock, inflammatory bowel diseases, chronic hepatitis, pulmonaryemphysema, acute respiratory distress syndrome, shock lung, cysticfibrosis, chronic bronchitis, glomerulonephritis and rheumatic arthritisas well as special tumors and tumor metastases.

None of said publications discloses that frankincense or hydrogenatedfrankincense products can be used for preventing and treating cerebralischemia and/or cranial/brain trauma. Nor can it be derived from theliterature that hydrogenated frankincense products are excellentlysuited for treating Alzheimer's disease.

It is thus an object of this invention to provide a medicament which canbe used successfully for preventing and/or treating cerebral ischemiaand/or cranial/brain trauma.

Another object of this invention is to provide a medicament which has ahigh bioavailability at the target organ and, along with an excellenteffectiveness in the treatment of cerebral ischemia and cranial/braintrauma, can be used in a particularly advantageous way for treatingAlzheimer's disease.

These objects are achieved by the subject matters of the claims.

The invention thus provides the use of frankincense, frankincenseextracts, substances contained in frankincense, the physiologicallyacceptable salts thereof, their derivatives and the physiologicallyacceptable salts thereof, pure boswellic acid, a physiologicallyacceptable salt of boswellic acid, a derivative of boswellic acid, asalt of a boswellic acid derivative or a boswellic acid-containingvegetable preparation for the production of a medicament for theprophylactic and/or therapeutic treatment of cranial/brain trauma and/orcerebral ischemia, on the one hand, and the use of the hydrogenationproducts of frankincense extracts, substances contained in frankincense,the physiologically acceptable salts thereof, their derivatives and thephysiologically acceptable salts thereof, pure boswellic acid, aphysiologically acceptable salt of boswellic acid, a derivative ofboswellic acid, a salt of a boswellic acid derivative or a boswellicacid-containing vegetable preparation for the production of a medicamentfor the prophylactic and/or therapeutic treatment of cerebral ischemia,cranial/brain trauma and/or Alzheimer's disease, on the other hand.

On account of their effectiveness in the prophylaxis and treatment ofcerebral ischemia, the medicaments can also be used advantageously forpreventing and treating cerebral lesions caused by apoplexy, cardiacinfarction or after an operation.

It was found surprisingly that frankincense, in particular frankincenseextracts, and substances contained in frankincense as well as thederivatives thereof, each in the salt form, where appropriate, and thehydrogenation products of the above compounds and active mixtures areexcellently suited for preventing and/or treating cerebral ischemia andcranial/brain trauma.

Different from the literature, it is not only frankincense andfrankincense extracts that can be used for treating Alzheimer's diseasebut also the above-mentioned hydrogenation products which in additionhave a good bioavailability.

Although as pointed out above frankincense and frankincense products areknown to be traditional natural drugs or medicaments for treatingdifferent psychic and physical conditions, the literature is silent onthe availability, existing at the target organ (site of action), of theactive substances contained therein. What is called the bioavailabilityis of special significance for the very prophylaxis and/or treatment ofdiseases pertaining to the brain. An active substance should be able topenetrate the blood-brain barrier, which may increase the effect andkeep constant or reduce the dosage of the medicament. In addition,resorption in the intestine has to be adequate.

According to the invention, preferably acetyl-11-keto-β-boswellic acid(AKBA), 11-keto-β-boswellic acid (KBA) and β-boswellic acid are used asboswellic acid. β-boswellic acid may contain small amounts of α- orγ-boswellic acid. β-boswellic acid can be obtained in known manner fromboswellic acid-containing plants, in particular from Boswellia serrata.Other suitable boswellia species are Boswellia papyrifera, Boswelliafrereana, Boswellia carteri, Boswellia thurifera or Boswellia glabra.Yet, other representatives of the boswellia family may also be used.

Physiologically acceptable salts of boswellic acid are preferablysodium, potassium, ammonium and calcium salts. Preferred derivatives ofboswellic acid are C₁-C₆ alkyl ester where the carboxyl group ofboswellic acid was esterified with a corresponding alcohol. Methylester, ethyl ester, n-propylester, iso-propyl ester, n-butyl ester,iso-butyl ester and tert.-butyl ester are preferred. It is also possiblefor the hydroxyl group of boswellic acid to be esterified with aphysiologically compatible carboxylic acid, preferably a C₁-C₂₀, inparticular a C₁-C₆, carboxylic acid, in particular with formic acid oracetic acid. Boswellic acid derivatives preferably used according to theinvention are β-boswellic acid acetate, β-boswellic acid formate,β-boswellic acid methyl ester, acetyl-β-boswellic acid,acetyl-11-keto-β-boswellic acid (AKBA) and 11-keto-β-boswellic acid(KBA).

According to the invention it is preferred to use vegetablepreparations, in particular frankincense or frankincense extracts forthe production of the medicaments for the prophylactic and/ortherapeutic treatment of cerebral ischemia and/or cranial/brain trauma.The extracts preferably contain one or more of the above-mentionedcompounds.

Thus, the use of frankincense or frankincense extracts, containingboswellic acid, in particular β-boswellic acid, for the production of amedicament for the prophylactic and/or therapeutic treatment of cerebralischemia and/or cranial/brain trauma is preferred according to theinvention.

Boswellic acids, in particular β-boswellic acid, can be obtained inknown manner from plants containing boswellic acid, in particular fromBoswellia serrata. Other suitable boswellia species are Boswelliapapyrifera, Boswellia frereana, Boswellia carteri, Boswellia thuriferaor Boswellia glabra. Yet, it is also possible to use otherrepresentatives of the boswellia family.

The frankincense used according to the invention or the frankincenseextracts used according to the invention (e.g. Salai Guggal) preferablycontain β-boswellic acid and/or acetyl-β-boswellic acid and/oracetyl-11-keto-β-boswellic acid and/or 11-keto-β-boswellic acid.

Vegetable preparations which can preferably be used according to theinvention for the production of the medicaments for the prophylacticand/or therapeutic treatment of cerebral ischemia and/or cranial/braintrauma, are commercially available, e.g. from the company of Ayurmedica,Pöcking, Germany, e.g. under the designation of H15. This is alipophilic extract from Boswellia serrata which contains an olibanum dryextract as the active substance. The product is available as a tablet oras granules. As shown in DE-A 44 44 288, a table contains 400 mgolibanum dry extract (4.2-5.9:1), extracting agent:chloroform/methanol.1 g granules contain 500 mg olibanum dry extract (4.2-5.9:1), extractingagent:chloroform/methanol.

However, other preparations containing frankincense extract can also beused according to the invention. In particular it is possible to useaccording to the invention synthetically produced or naturally collectedingredients of frankincense, in particular acetyl-11-keto-β-boswellicacid and/or 11-keto-β-boswellic acid and/or α-boswellic acid, optionallyin admixture with α- and/or γ-boswellic acid and/or one or more of theboswellic acid derivatives preferably used according to the invention,as described above, for the production of the medicament for theprophylactic and/or therapeutic treatment of cerebral ischemia and/orcranial/brain trauma according to the invention

The active substances and active substance compositions which arepreferred according to the invention and can be used for the productionof the medicaments for the prophylactic and/or therapeutic treatment ofcerebral ischemia and/or cranial/brain trauma, are described in DE-A 4444 288 and DE-A 44 45 728, for example, to which reference is made inthis respect. Boswellic acids and boswellic acid derivatives, preferredaccording to the invention, are also described in DE-A 42 01 903, towhich reference is also made in this respect.

The active substances and active substance compositions which aredescribed in DE-A 44 44 288 are preferred according to the invention.

A plant extract which was collected from frankincense, e.g. by ethanolicextraction, is also used preferably according to the invention

According to the invention the medicament for the prophylactic and/ortherapeutic treatment of cerebral ischemia and/or cranial/brain traumamay contain, in addition to the active substances defined herein andbased on frankincense, further active substances, in particular furthervegetable active substances.

According to the invention it was also found that the hydrogenationproducts of frankincense can be resorbed very well and penetrateadequately the blood-brain barrier so that an adequate active substanceconcentration can be achieved in the target organ, the activity of theproducts being substantially maintained, favorably even improved.

The hydrogenation products of frankincense, its ingredients and thephysiologically acceptable salts and derivatives of these hydrogenationproducts and also hydrogenated frankincense extracts are suited for theproduction of an inventive medicament for the prophylactic and/ortherapeutic treatment of cerebral ischemia, cranial/brain trauma and/orAlzheimer's disease.

Hydrogenation products of boswellic acid-containing vegetable extracts,boswellic acid, physiologically acceptable salts of boswellic acid,derivatives of boswellic acid, physiologically acceptable salts of thesederivatives, boswellic acid-containing vegetable preparations orketo-boswellic acid-containing vegetable extracts are also suitedaccording to the invention. Hydrogenation products of furtheringredients of frankincense, such as tirucallic acid or othertriterpenoid compounds, salts or derivatives thereof and vegetableextracts containing these compounds, are also suited.

The hydrogenation products of acetyl-11-keto-β-boswellic acid,11-keto-β-boswellic acid or β-boswellic acid are also suited accordingto the invention, wherein the latter may contain small amounts of α- orγ-boswellic acid. Hydrogenation products of β-boswellic acid acetate,β-boswellic acid formate, β-boswellic acid methyl ester,acetyl-β-boswellic acid and boswellic acids and derivatives of boswellicacids which are described in DE-A 42 01 903, to which reference is madein this respect, are also suited according to the invention.

Dihydroboswellic acids, their physiologically acceptable salts,derivatives thereof and physiological salts of the derivatives, inparticular β-dihydroboswellic acid acetate, β-dihydroboswellic acidformate, β-dihydroboswellic acid methyl ester, acetyl-β-dihydroboswellicacid, α-dihydroboswellic acid, acetyl-α-dihydroboswellic acid andformyl-α-dihydroboswellic acid can be used as hydrogenation productsaccording to the invention.

Keto-dihydroboswellic acids, their physiologically acceptable salts,derivatives thereof and physiological salts of the derivatives, inparticular acetyl-11-keto-β-dihydroboswellic acid,11-keto-β-dihydroboswellic acid or formyl-11-keto-β-dihydroboswellicacid are also suited according to the invention.

The hydrogenation products usable according to the invention can beobtained by hydrogenation, preferably by catalytic hydrogenation. Thesecompounds are hydrogenated in a manner known to a person skilled in theart, preferably such that the skeletal structure of the compound ishydrogenated selectively. Such a method is described in WO 02/15916, forexample.

A hydrogenated plant extract which is obtained from frankincense, e.g.by ethanolic extraction, can be used for the production of an inventivemedicament for the prophylactic and/or therapeutic treatment of cerebralischemia and/or cranial/brain trauma and/or Alzheimer's disease.

The sodium, potassium, ammonium and calcium salts of the above-mentionedcompounds are to be physiologically acceptable salts of thehydrogenation products according to the invention. The derivatives areto be in particular the C₁-C₆ alkyl esters of dihydroboswellic acidwhere the carboxyl group of dihydroboswellic acid was esterified with acorresponding alcohol. Such dihydroboswellic acid alkyl esters are e.g.the methyl ester, ethyl ester, n-propyl ester, iso-propyl ester, n-butylester, iso-butyl ester and tert.-butyl ester. It is also possible forthe hydroxyl group of dihydroboswellic acid to be esterified with aphysiologically compatible carboxylic acid, e.g. with a C₁ to C₂₀carboxylic acid, in particular with a C₁-C₆ carboxylic acid, inparticular with formic acid or acetic acid.

Vegetable preparations which can be used for the production of thehydrogenation products according to the invention, are commerciallyavailable, in particular from the company of Ayurmedica, Pöcking,Germany, e.g. under the designation of H15.

However, hydrogenation products of other preparations with frankincenseextract can also be used according to the invention. In particular it ispossible to use according to the invention hydrogenation products ofsynthetically produced or naturally collected ingredients offrankincense, in particular acetyl-11-keto-β-boswellic acid and/or11-keto-β-boswellic acid and/or β-boswellic acid, optionally inadmixture with α- and/or γ-boswellic acid and/or one or more of theboswellic acid derivatives preferably used according to the invention,as described above, for the production of the medicament.

Active substances and active substance compositions which are suitedaccording to the invention and can be used for the production of theinventive medicaments containing the hydrogenation products, aredescribed in WO 02/15916, for example, to which reference is made inthis respect.

In addition to the active substances defined herein and based onfrankincense, the medicament for the prophylactic and/or therapeutictreatment of cerebral ischemia and/or cranial/brain trauma and/orAlzheimer's disease can contain further active substances, in particularfurther vegetable active substances, according to the invention.

However, hydrogenation products of other preparations containingfrankincense extract can also be used according to the invention. Inparticular it is possible to use according to the inventionhydrogenation products of synthetically produced or naturally obtainedingredients of frankincense, in particularacetyl-11-keto-β-boswellicacid and/or 11-keto-β-boswellic acid and/orβ-boswellic acid, optionally in admixture with α- and/or γ-boswellicacid and/or one or more of the boswellic acid derivatives preferablyused according to the invention, as described above, for the productionof the medicament.

Since the above frankincense products and the hydrogenated frankincenseproducts have a very low toxicity, their compatibility is usually good.Subject to the severity of the disease to be treated and furtherfactors, such as the duration of the disease, possible known patient'sincompatibilities, the patient's general condition, etc., the dosagescan easily be chosen by the attending physician. According to theinvention the medicament is preferably formulated such that it isavailable in unit doses which can be administered, preferably orally,once or several times daily, in particular one to four times per day.

According to the invention the medicaments can be formulated in knownmanner for common administration routes, e.g. as oral, parenteral,rectal, intranasal, intracranial or intrathecal administrations. Oral,parenteral, rectal and intranasal administrations are preferred herein.The formulations can also be made for inhalation or insufflation.Formulations for the intracranial or intrathecal administration are alsopossible

The medicaments according to the invention can be present in solid,semi-solid or liquid form, for example. They may be formulated astablets, granules or capsules, for example, which along with the activesubstance or the active substance extract also contain pharmaceuticallycompatible additives, such as binders, fillers, lubricants, blasting oroptionally wetting agents and which may be coated.

Medicaments present in the form of tablets or granules or pellets arepreferred according to the invention, the granules or pellets usuallybeing present in conventional capsules. Along with the active substanceor the active substance extract the granules or tablets containconventional pharmaceutically acceptable additives, such as binders,e.g. pregelatinized corn starch, polyvinyl pyrrolidone orhydroxypropylmethyl cellulose, fillers, such as lactose, saccharose,mannitol, corn starch, microcrystalline cellulose or calcium hydrogenphosphate, lubricants, such as stearic acid, polyethylene glycol,magnesium stearate, talcum or silicon dioxide, blasting agents, such aspotato starch, sodium starch glycolate or sodium carboxymethyl celluloseand in particular the known superdisintegrating agents and optionallywetting agents, such as sodium lauryl sulfate. Tablets, pellets orcapsules may be coated in known manner (e.g. with a water-soluble or anenteric coating) or they can be available without coating. Coatedtablets are preferred.

Furthermore, the medicaments may be available in a manner known to theperson skilled in the art as liquid preparations for the oraladministration. Liquid preparations for oral administration may bepresent as aqueous or oily solutions, syrups, elixiers, emulsions orsuspensions, for example. Formulations can also be available as dryproduct for reconstitution with a suitable solvent, in particular water.The production of such liquid preparations is also known and, whereappropriate, conventional additives may be present, which includesuspending agents, such as sorbitol, cellulose derivatives, glucose,sugar syrup, gelatin, aluminum stearate gel or hydrogenated cookingfats, emulsifiers, such as lecithin, gum Arabic or sorbitan monooleate,non-aqueous carriers, such as almond oil, oily esters, ethyl alcohol orfractionated vegetable oils, preservatives, such as methyl orpropyl-para-hydroxybenzoate or sorbic acid, buffers, gustatorysubstances and flavoring agents, coloring substances and sweeteningagents.

Medicaments according to the invention can also be formulated in knownmanner as preparations for injections. Preparations preferred accordingto the invention are preparations for injections, in particular for theintravenous, intramuscular, subcutaneous, intrathecal or intracranialinjection, which are suitably available in unit dose form, such asampoules, or in multiple-dose containers. The formulations optionallycontain a conventional preservative and further conventional auxiliarysubstances. The medicaments according to the invention can also beprepared as suspensions, solutions or emulsions in oily or aqueouscarriers in a manner known to the person skilled in the art. Forexample, the preparations may be available as suspensions, solutions oremulsions in oily or aqueous carriers and contain conventional auxiliarysubstances, such as suspending, stabilizing and/or dispersing agentsand/or agents for adjusting the tonicity. Here, the agent can also bepresent as a dry powder for reconstitution in a suitable carrier.

Liquid sprays, nose drops or snuff powder can be mentioned as intranasalmedicaments.

If the administration is to be effected by inhalation, the compounds areprovided e.g. as an aerosol spray. For example, the compounds orextracts according to the invention may be available using suitablepropellants in pressurized packs. In this case, the pack will alsocontain a suitable dosing apparatus. Capsules or cartridges made ofgelatin, for example, for use in an inhalation means or an insufflationmeans may be prepared conventionally by using a powder mixture of acompound used according to the invention and a suitable powdery parentsubstance, such as lactose or starch.

Examples of suitable formulations and processes for the productionthereof are found in DE-A 44 44 288 and DE-A 44 45 728, to the fullcontents of which reference is made in this respect. In particular,reference is made to the examples of DE-A 44 44 288. The medicaments canbe formulated correspondingly according to the invention.

The neuroprotective effect of frankincense extract containing boswellicacid on the infarct volume after experimentally induced transient focalcerebral ischemia (apoplexy) was checked as follows.

Experimental Induction of a Focal Ischemia by IntracerebralMicroinjection of Endothelin 1 in the Vicinity of the Middle CerebralArtery (eMCAO)

Sprague Dawley rats (250-280 g) are clamped into a stereotactic deviceof the head under halothane inhalation narcosis and the skin is openedin the cranial center. A hole (1 mm in diameter) is drilled into thecranial bone using a dental drill in accordance with the coordinates:0.90 mm anterior bregma, 5.2 mm lateral relative to satura sagittalis. AHamilton syringe is then immersed to a depth of 7.5 mm into the brainfrom the dura mater and 3 μl (90 pmol) endothelin 1 is injected into thevicinity of the middle cerebral artery. Endothelin 1 has avasoconstrictive effect so that the vessel is closed and apoplexy isinduced. After 5 minutes, the syringe is removed and the skin above thecranial bone is sutured. The animals are held normothermically duringthe entire operation.

Experimental Groups:

Group 1: (n=8) eMCAO and frankincense extract (10 mg/kg,intraperitoneal, i.p., injection) 2 h before ischemia is induced, 6 h(10 mg/kg, i.p.) after the reperfusion, on day 3 (10 mg/kg, i.p.) and onday 6 (10 mg/kg, i.p.).

Group 2: (n=8) eMCAO and solvent (0.9% NaCl with 10% ethanol) i.p.injection as described in group 1.

Group 3: (n=8) mock-operated control group.

Group 4: (n=8) mechanical lesion induced by the injection channel of theHamilton syringe.

Determining the Infarct Volume:

Having survived for 7 days, the animals are perfusion-fixed in deeppentobarbital narcosis using 4% paraformaldehyde in 0.1 M phosphatebuffer. The brains are removed and coronal sections having a thicknessof 1 mm are made in a rat brain matrix. Following cryoprotection in 30%sucrose, cryostat sections having a thickness of 20 μm are made, placedon slides and stained using toluidine Nissl. The cortical and striatalinfarct centers are determined by means of a light microscope (Nikon,Eclipse TE 3000) with the image analysis software Lucia version 4.2.1,and the infarct volume is calculated by multiplication with the sectionthickness. The data is analyzed by means of the student's t-test forstatistical significance.

Results:

When the middle cerebral artery is obstructed, nerve cells in the braincenters of cortex and striatum die off. 7 days after the induction ofcerebral ischemia and parallel administration of frankincense extract, amarked and significant reduction of the infarct volume can be observedin comparison with the untreated control group. This finding issurprising and novel.

Hence it has been proved that the medicaments produced according to theinvention can reduce the lesion of cerebral tissue and resultingneurological peculiarities on account of an ischemia or can prevent sucha lesion.

The neuroprotective effect of frankincense extract containing boswellicacid on brain injuries was checked as follows.

Experimental Induction of a Traumatic Brain Injury

First, a traumatic brain injury was induced experimentally toexperimental animals in accordance with what is called the fluidpercussion method. To this end, Sprague Dawley rats (250 to 280 g) wereclamped into a stereotactic device of the head under halothaneinhalation narcosis, and the skin was opened in the cranial center. Ahole of 5 mm (diameter) is drilled into the cranial bone of the rightcalotte between bregma and lambda by means of a dental drill, the duramater remaining intact. Via a plexiglass cylinder filled with isotonicsaline and connected with the trepanation hole, a defined metal weightdeflects the pin of the plexiglass cylinder. As a result, theintracranial pressure is rapidly increased so as to cause an injury ofcortical and striatal brain centers. Having induced the traumatic braininjury, the skin above the cranial bone is sutured. The animals wereheld normothermically during the entire operation.

Experimental Groups:

Four experimental groups comprising eight experimental animals each werecreated. Two hours before ischemia was induced, six hours after thereperfusion, on the third day after the operation and on the sixth dayafter the operation, group 1 was given intraperitoneally 10 mg/kgfrankincense extract each. Instead of the frankincense extract, group 2was given intraperitoneally an aqueous solution containing 10% ethanoland 0.9% sodium chloride, an administration scheme being used the sameas that of group 1. Group 3 was not treated—neither with frankincenseextract nor with solvent—and group 4 was a control group where noischemia was induced.

Determining the Trauma Volume:

Having survived for seven days, the animals were perfusion-fixed in deeppentobarbital narcosis using 4% paraformaldehyde in 0.1 M phosphatebuffer, and the infarct volume was determined. For this purpose, thebrains were removed and coronal sections having a thickness of 1 mm weremade in a rat brain matrix. Following cryoprotection in 30% sucrose,cryostat sections having a thickness of 20 μm were made, placed on aslide and stained using toluidine Nissl. The cortical and striatalinfarct centers were determined by means of a light microscope (Nikon,Eclipse TE 3000) with the image analysis software Lucia version 4.2.1,and the trauma volume was calculated by multiplication with the sectionthickness. The data was analyzed by means of the student's t-test forstatistical significance.

Results:

As a result of the experimentally induced brain trauma, nerve cells inthe brain centers of cortex and striatum died off. Seven days after theinduction of the cerebral ischemia and administration of frankincenseextract, a marked and significant reduction of the trauma-inducedlesions can be observed in comparison with the untreated control group.

Hence it has been proved that the medicaments produced according to theinvention can reduce the lesion of cerebral tissue and resultingneurological peculiarities on account of a cranial/brain trauma or canprevent such a lesion.

1. A method of treating and/or preventing a cranial/brain trauma and/orcerebral ischemia comprising the step of administering to a subject inneed thereof a medicament comprising an active ingredient selected fromthe group consisting of: frankincense, frankincense extracts, substancescontained in frankincense, their physiologically acceptable salts, theirderivatives, physiologically acceptable salts of said derivatives, pureboswellic acid, a physiologically acceptable salt of boswellic acid, aderivative of boswellic acid, a salt of a boswellic acid derivative, anda boswellic acid-containing vegetable preparation.
 2. The methodaccording to claim 1, wherein the cerebral ischemia occurs as a resultof apoplexy, cardiac infarction or an operation.
 3. The method accordingto claim 1, wherein the active ingredient comprises frankincense or aboswellic acid-containing vegetable extract.
 4. The method according toclaim 1, wherein the active ingredient is selected from the groupconsisting of a keto-boswellic acid, 3-O-acetyl-11-keto-β-boswellicacid, 11-keto-β-boswellic acid, a physiologically acceptable salt of aketo-boswellic acid, a derivative of a keto-boswellic acid, a salt of aketo-boswellic acid derivative, and a keto-boswellic acid-containingvegetable extract.
 5. The method according to claim 1, wherein theactive ingredient comprises a tirucallic acid, another triterpene or asalt or derivative thereof or a vegetable extract containing atirucallic acid, another triterpene or a salt or derivative thereof. 6.The method according to claim 1, wherein the active ingredient comprisesan extract from a Boswellia serrata resin.
 7. A method of treatingand/or preventing a cranial/brain trauma, cerebral ischemia and/orAlzheimer's disease comprising the step of administering to a subject inneed thereof a medicament comprising an active ingredient selected fromthe group consisting of: hydrogenation products of frankincenseextracts, substances contained in frankincense, their physiologicallyacceptable salts, their derivatives, physiologically acceptable salts ofsaid derivatives, pure boswellic acid, a physiologically acceptable saltof boswellic acid, a derivative of boswellic acid, a salt of a boswellicacid derivative, and a boswellic acid-containing vegetable preparation.8. The method according to claim 7, wherein the medicament is used forpreventing and/or treating Alzheimer's disease.
 9. The method accordingto claim 7, wherein the active ingredient comprises a hydrogenationproduct of a boswellic acid-containing vegetable extract.
 10. The methodaccording to claim 7, wherein the active ingredient comprises ahydrogenated extract from a Boswellia serrata resin.
 11. The methodaccording to claim 7, wherein the active ingredient is selected from thegroup consisting of a hydrogenation product of boswellic acid, aphysiologically acceptable salt of boswellic acid, a derivative thereof,a salt of a boswellic acid derivative, and a boswellic acid-containingvegetable preparation.
 12. The method according to claim 7, wherein theactive ingredient comprises dihydroboswellic acid.
 13. The methodaccording to claim 7, wherein the active ingredient comprises ahydrogenation product selected from the group consisting ofβ-dihydroboswellic acid acetate, β-dihydroboswellic acid formate,β-dihydroboswellic acid methyl ester, acetyl-β-dihydroboswellic acid,α-dihydroboswellic acid, acetyl-α-dihydroboswellic acid andformyl-α-dihydroboswellic acid.
 14. The method according to claim 7,wherein the active ingredient is selected from the group consisting of aketo-dihydroboswellic acid, acetyl-11-keto-β-dihydroboswellic acid,11-keto-β-dihydroboswellic acid, formyl-11-keto-β-dihydroboswellic acid,a physiologically acceptable salt of a keto-dihydroboswellic acid, aderivative of a keto-dihydroboswellic acid, a salt of aketo-dihydroboswellic acid derivative, and a hydrogenated keto-boswellicacid-containing vegetable extract.
 15. The method according to claim 7,wherein the active ingredient is selected from the group consisting of ahydrogenation product of tirucallic acid, a salt of said hydrogenationproduct, a derivative of said hydrogenation product or salt thereof, anda hydrogenated tirucallic acid-containing vegetable extract.
 16. Themethod according to claim 1, wherein the medicament is formulated forintraperitoneal, oral, buccal, rectal, intramuscular, topical,subcutaneous, intraarticular, intravenous, intrathecal or intracranialadministration.
 17. The method according to claim 1, wherein themedicament comprises a tablet or solution.
 18. The method according toclaim 7, wherein the medicament is formulated for intraperitoneal, oral,buccal, rectal, intramuscular, topical, subcutaneous, intraarticular,intravenous, intrathecal or intracranial administration.
 19. The methodaccording to claim 7, wherein the medicament comprises a tablet orsolution.